Posttraumatic stress disorder (PTSD) is associated with cognitive deficits in attention/working memory, executive functions, episodic memory, and inhibitory control. Understanding the nature of cognitive deficits, especially in attention/working memory, is important, as problems with these abilities have been shown to critically affect successful everyday functioning (e.g., occupational functioning) in PTSD. We hypothesize that one contributing factor to these attention problems involves a breakdown in performance when individuals with PTSD experience increasing working memory loads and, especially, capacity overload in working memory systems, a process that may be moderated by limbic networks (e.g., amygdala). Previous neuroimaging studies in PTSD have examined dysfunction in these networks using symptom provocation paradigms, but these studies have largely ignored the significant cognitive processing deficits associated with PTSD, which may contribute to this dysfunction through cognitive overload-induced effects. The proposed study aims to capture in vivo the brain activation changes involved in the response to and recovery from working memory overload in individuals with PTSD. Based on prior research in healthy individuals, susceptibility to such overload-induced effects are likely to have significant effects on subsequent cognitive function, which may help explain the persistent attention and memory deficits experienced by a subgroup of individuals with PTSD. Thus, the proposed study also aims to examine the relationship of response to and recovery from cognitive overload with clinical measures of neuropsychological performance and with daily functioning outcomes. The objective of this CDA-2 application is therefore to gain further expertise in neuroimaging research methods, specifically in functional magnetic resonance imaging (fMRI), and their application to studying cognitive processes in neuropsychiatric illness. This will be accomplished through a rigorous program of training, collaboration with other neuroimaging and traumatic stress researchers, and a novel, theory-driven study utilizing fMRI to examine response to and recovery from working memory overload in PTSD. In the proposed study, 30 Veterans with PTSD and 30 trauma-exposed (i.e., combat) Veterans without PTSD will undergo behavioral, neuropsychological, and fMRI assessments. The key questions in this study are whether individuals with PTSD are more vulnerable to the effects of working memory overload and to poor recovery from this cognitive overload, and what underlying neural mechanisms contribute to this vulnerability. Secondary questions address the relationship of this overload-induced response to clinical neuropsychological performance in attention and memory, to physiological measures of stress regulation, and to functional outcomes in PTSD. Findings from this study may provide critical insights into the specific mechanisms underlying brain dysfunction and cognitive processing difficulties in PTSD. Moreover, understanding the mechanisms and dynamics related to overload-induced effects in neural systems may provide valuable knowledge regarding the physiologic processes by which loss of cognitive control can lead to adaptive or maladaptive behavioral changes in PTSD. Knowledge of these mechanisms may enable more directed development and testing of novel therapies for PTSD. PUBLIC HEALTH RELEVANCE: Project Narrative Current epidemiological research shows that 10-25% of Veterans will be diagnosed with PTSD in their lifetime, resulting in significant functional impairment (e.g., occupational difficulties). Although the contributions of cognitive deficits to these functional difficulties is coming into better focus, understanding the dynamics and underlying mechanisms contributing to cognitive processing difficulties in PTSD is essential to developing effective treatments to counteract the impact of these difficulties. The proposed study aims to increase understanding of the neural correlates of working memory overload and recovery from this overload in individuals with PTSD, which may provide valuable insights into the underlying neuroscience of PTSD and help increase valuable knowledge of the specific mechanisms contributing to brain dysfunction associated with the effects of traumatic stress. Moreover, results from this study may enable more directed development and testing of novel therapies for the many Veterans with PTSD for whom existing treatments are inadequate.